Human Liver-Derived Stem Cells Improve Fibrosis and Inflammation Associated with Nonalcoholic Steatohepatitis

Cell therapy may be regarded as a feasible alternative to whole organ transplantation to treat end-stage liver diseases. Human liver stem cells (HLSCs) are a population of cells easily obtainable and expandable from a human adult liver biopsy. HLSCs share with mesenchymal stromal cells the same phenotype, gene expression profile, and differentiation capabilities. In addition, HLSCs show a specific commitment to the hepatic phenotype. Injection of HLSCs into immunodeficient mice fed with a methionine-choline-deficient diet to induce nonalcoholic steatohepatitis ameliorates liver function and morphology. In particular, HLSC treatment induced a reduction of liver fibrosis and inflammation at morphological and molecular levels. Moreover, HLSCs were able to persist for up to 3 weeks after the injection. In conclusion, HLSCs have healing effects in a model of chronic liver disease.

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Amnion-Derived Mesenchymal Stromal/Stem Cell Paracrine Signals Potentiate Human Liver Organoid Differentiation: Translational Implications for Liver Regeneration

Frontiers in Medicine ◽

10.3389/fmed.2021.746298 ◽

2021 ◽

Vol 8 ◽

Author(s):

Antonio Lo Nigro ◽

Alessia Gallo ◽

Matteo Bulati ◽

Giampiero Vitale ◽

Diego Sebastian Paini ◽

...

Keyword(s):

Stem Cells ◽

Cell Differentiation ◽

Liver Regeneration ◽

Conditioned Medium ◽

Liver Diseases ◽

Human Liver ◽

Progenitor Cell ◽

Liver Repair ◽

Liver Organoids ◽

End Stage

The prevalence of end-stage liver diseases has reached very high levels globally. The election treatment for affected patients is orthotopic liver transplantation, which is a very complex procedure, and due to the limited number of suitable organ donors, considerable research is being done on alternative therapeutic options. For instance, the use of cell therapy, such as the transplantation of hepatocytes to promote liver repair/regeneration, has been explored, but standardized protocols to produce suitable human hepatocytes are still limited. On the other hand, liver progenitor and multipotent stem cells offer potential cell sources that could be used clinically. Different studies have reported regarding the therapeutic effects of transplanted mesenchymal stromal/stem cells (MSCs) on end-stage liver diseases. Moreover, it has been shown that delivery of MSC-derived conditioned medium (MSC-CM) can reduce cell death and enhance liver proliferation in fulminant hepatic failure. Therefore, it is believed that MSC-CM contains many factors that probably support liver regeneration. In our work, we used an in vitro model of human liver organoids to study if the paracrine components secreted by human amnion-derived MSCs (hAMSCs) affected liver stem/progenitor cell differentiation. In particular, we differentiated liver organoids derived from bipotent EpCAM+ human liver cells and tested the effects of hAMSC secretome, derived from both two-dimensional (2D) and three-dimensional (3D) hAMSC cultures, on that model. Our analysis showed that conditioned medium (CM) produced by 3D hAMSCs was able to induce an over-expression of mature hepatocyte markers, such as ALB, NTCP, and CYP3A4, compared with both 2D hAMSC cultures and the conventional differentiation medium (DM). These data were confirmed by the over-production of ALB protein and over-activity of CYP3A4 observed in organoids grown in 3D hAMSC-CM. Liver repair dysfunction plays a role in the development of liver diseases, and effective repair likely requires the normal functioning of liver stem/progenitor cells. Herein, we showed that hAMSC-CM produced mainly by 3D cultures had the potential to increase hepatic stem/progenitor cell differentiation, demonstrating that soluble factors secreted by those cells are potentially responsible for the reaction. This work shows a potential approach to improve liver repair/regeneration also in a transplantation setting.

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Evolving Cell-Based and Cell-Free Clinical Strategies for Treating Severe Human Liver Diseases

Cells ◽

10.3390/cells9020386 ◽

2020 ◽

Vol 9 (2) ◽

pp. 386 ◽

Cited By ~ 4

Author(s):

Viviana Cernigliaro ◽

Rossella Peluso ◽

Beatrice Zedda ◽

Lorenzo Silengo ◽

Emanuela Tolosano ◽

...

Keyword(s):

Stem Cells ◽

Liver Transplantation ◽

Extracellular Vesicles ◽

Liver Diseases ◽

Adult Stem Cells ◽

Embryonic Stem ◽

Hepatic Function ◽

Bioactive Molecules ◽

Cell Based Therapy ◽

End Stage

Liver diseases represent a major global health issue, and currently, liver transplantation is the only viable alternative to reduce mortality rates in patients with end-stage liver diseases. However, scarcity of donor organs and risk of recidivism requiring a re-transplantation remain major obstacles. Hence, much hope has turned towards cell-based therapy. Hepatocyte-like cells obtained from embryonic stem cells or adult stem cells bearing multipotent or pluripotent characteristics, as well as cell-based systems, such as organoids, bio-artificial liver devices, bioscaffolds and organ printing are indeed promising. New approaches based on extracellular vesicles are also being investigated as cell substitutes. Extracellular vesicles, through the transfer of bioactive molecules, can modulate liver regeneration and restore hepatic function. This review provides an update on the current state-of-art cell-based and cell-free strategies as alternatives to liver transplantation for patients with end-stage liver diseases.

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Therapeutic applications of bone marrow-derived stem cells in liver transplantation for end-stage liver diseases

Chinese Science Bulletin ◽

10.1007/s11434-007-0392-9 ◽

2007 ◽

Vol 52 (18) ◽

pp. 2449-2456

Author(s):

HaiYing Luo ◽

YunFang Wang ◽

Wei Kong ◽

XueTao Pei

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Liver Transplantation ◽

Liver Diseases ◽

Therapeutic Applications ◽

End Stage

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A subset of human rapidly self-renewing marrow stromal cells preferentially engraft in mice

Blood ◽

10.1182/blood-2005-07-2701 ◽

2006 ◽

Vol 107 (5) ◽

pp. 2153-2161 ◽

Cited By ~ 96

Author(s):

Ryang Hwa Lee ◽

Shu Ching Hsu ◽

James Munoz ◽

Jin Sup Jung ◽

Na Rea Lee ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Progenitor Cells ◽

Stromal Cells ◽

Adult Stem Cells ◽

Tissue Injury ◽

Marrow Stromal Cells ◽

Immunodeficient Mice ◽

Adult Mice

Controversies have arisen as to whether adult stem cells or progenitor cells from bone marrow can engraft into nonhematopoietic tissues in vivo. To resolve some of the controversies, we developed a highly sensitive polymerase chain reaction-based single nucleotide polymorphism (PCR-SNP) assay for competitive engraftment of mixtures of stem/progenitor cells. We used the assay to follow engraftment in immunodeficient mice of subpopulations of the stem/progenitor cells from human bone marrow referred to as either mesenchymal stem cells or marrow stromal cells (MSCs). The engraftment into adult mice without induced tissue injury was low and variable, but there was preferential engraftment of a subpopulation of rapidly self-renewing MSCs (RS-MSCs) compared with a subpopulation of slowly renewing MSCs (SR-MSCs). After intravenous infusion, there was a tendency for the cells to engraft into the hippocampal region that was previously designated a “vascular niche.” Migration assays suggested that preferential engraftment of RS-MSCs was in part explained by their expression of CXCR4 and CX3R1, the receptors for SDF-1 and fractalkine.

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Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope?

Cells ◽

10.3390/cells8101127 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1127 ◽

Cited By ~ 6

Author(s):

Irina V. Kholodenko ◽

Leonid K. Kurbatov ◽

Roman V. Kholodenko ◽

Garik V. Manukyan ◽

Konstantin N. Yarygin

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Therapy ◽

Progenitor Cells ◽

Liver Tissue ◽

Liver Diseases ◽

Human Liver ◽

Chronic Liver ◽

Attractive Alternative ◽

Short Supply

Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects—expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications.

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Modeling and therapy of human liver diseases using induced pluripotent stem cells: How far have we come?

Hepatology ◽

10.1002/hep.24143 ◽

2011 ◽

Vol 53 (2) ◽

pp. 708-711 ◽

Cited By ~ 11

Author(s):

Alejandro Soto-Gutierrez ◽

Edgar Tafaleng ◽

Victoria Kelly ◽

Jayanta Roy-Chowdhury ◽

Ira J. Fox

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Liver Diseases ◽

Human Liver ◽

Induced Pluripotent

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In VitroandIn VivoHepatic Differentiation of Adult Somatic Stem Cells and Extraembryonic Stem Cells for Treating End Stage Liver Diseases

Stem Cells International ◽

10.1155/2015/871972 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 20

Author(s):

Chenxia Hu ◽

Lanjuan Li

Keyword(s):

Stem Cells ◽

Liver Tissue ◽

Liver Diseases ◽

Embryonic Stem ◽

Somatic Stem Cells ◽

Hepatic Differentiation ◽

Short Supply ◽

End Stage ◽

Promising Source

The shortage of liver donors is a major handicap that prevents most patients from receiving liver transplantation and places them on a waiting list for donated liver tissue. Then, primary hepatocyte transplantation and bioartificial livers have emerged as two alternative treatments for these often fatal diseases. However, another problem has emerged. Functional hepatocytes for liver regeneration are in short supply, and they will dedifferentiate immediatelyin vitroafter they are isolated from liver tissue. Alternative stem-cell-based therapeutic strategies, including hepatic stem cells (HSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), are more promising, and more attention has been devoted to these approaches because of the high potency and proliferation ability of the cells. This review will focus on the general characteristics and the progress in hepatic differentiation of adult somatic stem cells and extraembryonic stem cellsin vitroandin vivofor the treatment of end stage liver diseases. The hepatic differentiation of stem cells would offer an ideal and promising source for cell therapy and tissue engineering for treating liver diseases.

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